Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
A claim amendment was filed on 01/15/2026, Claims 2 and 10-14 are canceled. Claims 1 and 3-9 are pending and under consideration in this action.
The rejection of claims 1, and 3-9 under 35 U.S.C. 112(a) as failing to comply with the written description requirement is withdrawn in light of the amendment.
The rejection of claims 3-9 under 35 U.S.C. 112(b) as being indefinite is withdrawn in light of the amendment.
Priority
The instant claims are entitled to an effective filing date of 02/28/2020.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
(Maintained) Claim 1 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is indefinite because it is unclear whether the claim intends to reference the same bacteria present in the urine sample throughout the claim. The claim requires generating a microbial profile of the bacteria present in a urine sample obtained from the subject. Then, the claim requires conducting a different abundance analysis of “the bacteria” present in a stool and/or urine sample. It is unclear whether the claim intends to broaden the scope of the sample from a urine sample to a stool and/or urine, and consequently it is unclear whether the bacteria are required to be present in urine.
Response to Arguments
Applicant's arguments filed 01/15/2026 have been fully considered but they are not persuasive.
§112(b) rejection of claim 1
Applicant argues that the amendment filed 01/15/2026 addresses the amendment. See the last paragraph on page 4 of the remarks.
This argument is not persuasive because it is still unclear whether claim 1 requires generating a microbial profile and conducting a differential abundance analysis on the same bacteria. To clarify, claim 1 recites “generating a microbial profile of the bacteria present in a urine sample obtained from the subject” in line 2. Then, the claim requires conducting a differential abundance analysis of the OTUs in “the bacteria present in a stool and/or urine sample obtained from the subject” (lines 8-9). The claim refers to the same subject, but different samples throughout the claim, i.e. urine vs. stool and/or urine samples. As such, there are multiple reasonable claim interpretations. In the first interpretation, claim 1 requires generating a microbial profile of the bacteria present in a subject’s urine sample, and then separately conducting a differential abundance analysis on different bacteria present in the subject’s stool and/or a urine sample. In the second interpretation, claim 1 requires generating a microbial profile and conducting a differential analysis on the same urine sample. Consequently, one of ordinary skill in the art cannot ascertain the metes and bounds of the required bacteria. To obviate this rejection, “a urine sample” recited in line 3 can be replaced with “a stool and/or urine sample”, and “a stool and/or urine sample” in line 8 can be replaced with “the stool and/or urine sample”.
Claim Interpretation
Claim 1 requires 7 active method steps. First, a microbial profile of bacteria present in a urine sample is generated using 16S RNA or shotgun metagenomic sequencing. Second, a differential abundance analysis of the OTUs associated with oxalate metabolism is conducted. The way in which the OTUs are associated with oxalate metabolism is not limited. The instant specification suggests the networks of bacteria responsible for oxalate metabolism in humans have not been identified; but the specification also suggests that Oxalobacter formigenes degrades oxalate, preventing its absorption into circulation. See [0005]. Therefore, bacteria taxa/OTUs associated with O. formigenes could reasonably be considered associated with oxalate metabolism as well. Third, a differential abundance analysis of bacteria is conducted on the bacteria present in a subject’s urine sample. Fourth, a ratio of bacteria is determined between bacteria associated with health and bacteria associated with urinary stone disease (USD) or hyperoxaluria present in the subject’s urine sample. Fifth, a risk level for developing USD or hyperoxaluria is assigned based on the ratio. According to the instant specification urinary stone disease or USD is also known as kidney stones or urolithiasis [0041]. Sixth, determining the type of bacteria associated with health that are either missing or diminished using the subject’s stool and/or urine. Seventh, administering a composition comprising one or more of the missing or diminished types of bacteria to the subject.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
(Maintained) Claims 1, 3-4, and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Zampini (Scientific reports, 2019, 9(1), 5425) in view of Campieri (Kidney international, 2001 60(3), 1097-1105). The underlined text is relevant to the amendment.
Regarding claim 1, Zampini teaches collecting voided, clean-catch mid-stream urine from subjects. See the third paragraph on page 9. Subjects include patients who had an active episode of urinary stone disease (USD) and control subjects without a history of USD. See the second paragraph on page 9. Zampini teaches extracting DNA from the urine samples for sequencing of the V4 region of the 16S rRNA gene. See the second to last paragraph on page 9. Zampini teaches conducting a differential abundance analysis through a Wald test. The relative abundance of OTUs is corelated to the relative abundance of O. formigenes. See the first paragraph on page 10. Zampini discloses that bacteria from the Enterobacteriaceae family have a strong association with the urinary tract of the USD cohort. See the first passages on pages 8 and 9. As disclosed in supplementary table S1, urine from USD patients include 31 OTUs from the Enterobacteriaceae family, while Enterobacteriaceae is absent in the urine from healthy patients. Thus, Zampini indicates that the risk of stone formation is associated with the 0:31 ratio of the 0 Enterobacteriaceae OTUs in healthy urine, as compared to the 31 OTUs present in the urine of USD patients. In contrast to the disease-causing Enterobacteriaceae, Zampini discloses that bacteria from the Lactobacillus genus are frequently found in the urinary tract of healthy individuals. See the sentence spanning pages 1-2. Zampini discloses that what differentiates the healthy cohort from the USD cohort is primarily the loss of Lactobacillus from the urinary tract of healthy population. See the last sentence on page 3. As disclosed in table S1, urine from the healthy cohort includes 100 OTUs from the Lactobacillus genus, as compared to the 1 OTU found in urine from the USD cohort.
Zampini does not teach administering a composition comprising one or more of the missing or diminished types of bacteria to the subject.
Campieri teaches six patients with idiopathic calcium-oxalate urinary stone disease and mild hyperoxaluria. See the patients section on page 1098. Each patient receives 4 g/day of freeze-dried lactic acid bacteria for four weeks. Each gram of the mixture includes Lactobacillus acidophilus, Lactobacillus plantarum, and Lactobacillus brevis. The preparation is administered twice per day before meals after suspension in cold water. See the design of the study section on page 1099. Campieri discloses feeding the mixture of freeze-dried lactic acid bacteria leads to a significant reduction of the urinary excretion of oxalate in a group of patients with idiopathic calcium-oxalate urolithiasis (i.e. USD) and mild hyperoxaluria. See the second paragraph in the left column on page 1102. The urine load of oxalate plays a pivotal role in calcium-oxalate stone formation. See the first two lines in the right column of page 1097 after the abstract.
It would have been obvious to a person ordinary skill in the art prior to the effective filing date of the instantly claimed invention to apply the lactic acid bacteria administration technique of Campieri to the USD patients of Zampini. Doing so is merely the application of known techniques. One would be motivated to do so because Campieri suggests that administering the freeze-dried lactic acid bacteria mixture containing Lactobacillus can reduce the urinary excretion of oxalate in patients with USD. There would be a reasonable expectation of success because Zampini and Campieri teach patient populations with USD.
Regarding claims 3-4 and 6, Zampini teaches urine from subjects. See the third paragraph on page 9. Subjects include patients (i.e. humans) and controls without a history of USD. See the second paragraph on page 9. Zampini teaches extracting DNA from the urine samples for sequencing of the V4 region of the 16S rRNA gene. See the second to last paragraph on page 9. Zampini teaches conducting a differential abundance analysis through a Wald test. The relative abundance of OTUs is corelated to the relative abundance of O. formigenes. See the first paragraph on page 10. Zampini discloses that bacteria from the Lactobacillus genus are frequently found in the urinary tract of healthy individuals. See the sentence spanning pages 1-2. As disclosed in table S1, urine from the healthy cohort includes 100 OTUs from the Lactobacillus genus, as compared to the 1 OTU found in urine from the USD cohort (i.e. 100:1 ratio). Zampini discloses that what differentiates the healthy cohort from the USD cohort is primarily the loss of Lactobacillus from the urinary tract of healthy population (e.g. risk level). See the last sentence on page 3. Thus, Zampini indicates that the Lactobacillus genus is associated with health and diminished in the USD subjects’ urine.
Zampini does not teach quantifying oxalate-degrading microbiome functional genes to determine oxalate-degrading capacity (relevant to instant claim 3)
Zampini does not teach administering a composition comprising one or more of the missing or diminished types of bacteria to the subject (relevant to instant claim 3).
Zampini does not explicitly teach one or more missing or diminished bacteria that are selected from a group that includes Lactobacillus helveticus and Lactobacillus plantarum, because Zampini indicates that all species within the Lactobacillus genus are associated with health (relevant to instant claims 4 and 6).
Campieri teaches administering a freeze-dried lactic acid bacteria mixture containing Lactobacillus plantarum to patients with idiopathic calcium-oxalate urinary stone disease and mild hyperoxaluria. See the ‘patients’ section on page 1098 and ‘the design of the study’ section on page 1099. Campieri discloses feeding the mixture of freeze-dried lactic acid bacteria leads to a significant reduction of the urinary excretion of oxalate. See the second paragraph in the left column on page 1102. Furthermore, Campieri teaches studying the presence of OxlT, frc, and oxc genes in lactic acid bacteria by means of PCR amplification of genomic DNA using specific primers. See the right column on page 1099. Campieri discloses some lactic acid bacteria are able to degrade oxalate. However, Campieri discloses that no amplification products (e.g. a 0 quantification) for the three genes are observed from Streptococcus thermophilus, Lactobacillus acidophilus, Bifidobacterium infantis, Lactobacillus plantarum, and Lactobacillus brevis genomic DNA. See figure 1 and the first paragraph on page 1101. Thus, Campieri teaches quantifying oxalate-degrading microbiome functional genes of Lactobacillus species.
It would have been obvious to a person ordinary skill in the art prior to the effective filing date of the instantly claimed invention to apply the lactic acid bacteria administration technique of Campieri to the USD patients of Zampini. One would be motivated to administer the freeze-dried lactic acid bacteria of Campieri to the USD patients of Zampini because Campieri suggests that administering the freeze-dried lactic acid bacteria mixture containing Lactobacillus can reduce the urinary excretion of oxalate in patients with USD. There would be a reasonable expectation of success because Zampini and Campieri teach patient populations with USD, and Zampini suggests that Lactobacillus in the urinary tract is associated with health.
(Maintained) Claims 5 and 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Zampini (Scientific reports, 2019, 9(1), 5425) in view of Campieri (Kidney international, 2001 60(3), 1097-1105), as applied to claims 1-4, 6, 10-12 and 14 above, and further in view of Miller (MSystems, 2017, 2(5), 10-1128; as previously relied upon), hereafter Miller (2017), with evidence from Miller (Applied and environmental microbiology, 2016, 82(9), 2669-2675) hereafter Miller (2016).
The teachings of Zampini and Campieri with respect to claims 3 and 4 are discussed above.
Regarding claims 5 and 9, Zampini discloses that the urine from the healthy cohort includes 100 OTUs from the Lactobacillus genus, as compared to the 1 OTU found in urine from the USD cohort (i.e. 100:1 ratio). Moreover, urine from the healthy cohort includes 1 OTU from the Ruminococcaceae family, whereas the Ruminococcaceae family is absent in the urine from the USD cohort (i.e. 1:0 ratio). Thus, Zampini indicates that the Lactobacillus genus and Ruminococcaceae family are associated with health but diminished or missing respectively in the urine of USD patients.
Zampini and Campieri do not explicitly teach one or more missing or diminished bacteria that are selected from a group that includes the bacteria falling under the genus Ruminococcus genus, because Zampini indicates that all genera and species within the Ruminococcaceae family are associated with health (relevant to instant claim 5).
Zampini and Campieri do not teach one or more missing or diminished bacteria that are obtained from Neotoma albigula (relevant to instant claim 9).
Miller (2017) teaches developing targeting bacteriotherapies to reduce urinary oxalate excretion in patients at risk for recurrent calcium oxalate stones. See the last sentence of the abstract. Miller (2017) teaches transplanting NA feces, that is, the whole fecal microbial community from N. albigula into a model mammalian host, the Sprague-Dawley rat. See the first paragraph of the results section on page 2. Miller (2017) discloses that the NA bacteria include Lactobacillus reuteri, L. animalis, L. johnsonii, gasseri, and Enterococcus gallinarum. See table 3. Evidentiary reference Miller (2016) discloses that Ruminococcus is prevalent in the N. albigula gut. See the first passage in the right column on page 2669 of Miller (2016). Miller (2017) teaches that Ruminococcus is positively correlated with the relative abundance of Oxalobacteraceae. See table S1. The N. albigula (NA) feces group of Miller (2017) exhibits a 66% reduction in urinary oxalate after 3 days of consecutive transplants, which is on par with studies that administer daily oral doses of O. formigenes for up to 4 weeks. See the first paragraph of the discussion section.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to further apply the N. albigula transplant technique of Miller (2017) to the USD patients of Zampanini in the method of Zampanini and Campieri discussed above. One would be motivated to administer the N. albigula feces of Miller (2017) because Miller (2017) discloses that the N. albigula feces reduce urinary oxalate concentrations. Moreover, the N. albigula feces includes Lactobacillus, as evidenced by Miller (2017), and Ruminococcus, as evidenced by Miller (2016); both of which are diminished or missing in the urine of the USD patients of Zampanini. There would be a reasonable expectation of success because Miller (2017) demonstrates administering the feces to a model mammal.
Regarding claim 7 and 8, Miller (2017) discloses that the animals are fed a 0.2% oxalate, high-fiber rabbit chow diet. Miller (2017) teaches preparing fecal transplants by grinding 1 g of fresh or autoclaved feces per day for each recipient from N. albigula donors with a sterile motor and pestle and adding it directly to the food. The negative control received autoclaved feces, while the NA feces group received fresh feces. See first two paragraphs of the ‘materials and methods’ section on page 9. Miller (2017) teaches a host mammalian host, the Sprague-Dawley rat (SDR). See the last paragraph on page 2. The global mean of oxalate intake for all SDR animals across all time points is 0.904 ± 0.009 g/kg body weight. See table 1. Moreover, Miller (2017) discloses that the animals are consuming 1.5% oxalate at each time point. i.e. before transplant, and after transplant. See the captions of figures 1-4. Thus, Miller (2017) teaches administering a composition comprising 0.2% oxalate (e.g. a prebiotic) rabbit chow and N. albigula feces containing Ruminococcus because evidentiary reference Miller (2016) discloses that Ruminococcus is prevalent in the N. albigula gut.
Response to Arguments
Applicant's arguments filed 01/15/2026 have been fully considered, but they are unpersuasive.
Applicant states “it is asserted that Zampini teaches the elements described for the anticipation rejection”. See the first paragraph on page 5 of the remarks.
However, none of the claims are rejected as being anticipated by Zampini.
Applicant argues that the instant claims require personalized treatment because claim 1 recites “determining the bacteria associated with health that are either missing or diminished in the subject’s urine sample; and administering to the subject a composition comprising one or more of the missing or diminished bacteria”. Applicant asserts that the rejection of claims 1, 3-4, 6, 10-12 and 14 should be withdrawn because personalized treatment is not taught, and is non-obvious in view of Zampini and Campieri. See the second paragraph on page 5 of the remarks.
This argument is not persuasive because every claimed element is taught by the prior art. Zampini teaches individuals with USD that have diminished Lactobacillus in their urine compared to healthy urine samples (see table S1), and Campieri teaches administering Lactobacillus to patients with USD (see the second paragraph in the left column on page 1102). As discussed in the rationale above, it would have been obvious to apply the Lactobacillus administration technique of Campieri to the USD individuals of Zampini. It is unclear, based on Applicant’s argument, how the personalized effect of the instantly claimed invention differs compared to the combined teachings of Zampini and Campieri. The fact that applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Applicant argues that neither Zampini nor Miller teach or suggest a personalized approach to the treatment or prevention of USD. Miller teaches transplanting N. albigula feces to prevent oxalate stone formation, but they do not teach how to modify treatment to tailor it to the needs of a specific subject. Because the claimed invention provides the significantly ability to tailor the treatment of the subject based on the data obtained, Applicants respectfully requires the rejection of claims 5 and 7-9 over Zampini in view of Miller be withdrawn. See the paragraph spanning pages 5-6.
This argument is not persuasive because one cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Claims 5 and 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Zampini, Campieri and Miller(2017), not Zampini and Miller (2017) alone. Although Applicant asserts that the references do not teach a personalized approach, Applicant has not pointed to a specific claim element that is not taught by the prior art references.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/K.C.B./Examiner, Art Unit 1657